Every year more than 30% (2 billion) of the world's population and 75 million adult Americans suffer from disorders that have been lumped under the term anxious misery. Among patients who receive treatment, a large number remain with debilitating symptoms, often for years or decades. Recently the NIMH has led efforts to define constructs within the Negative Valence System (NVS) that cut across such disorders in order to spur research on underlying mechanisms. This application will focus on potential brain circuitry and behaviors associated with loss, and responses to sustained threat, two of the most central NVS dimensions. By considering these brain circuits jointly, we can disentangle these dimensions for more specific targeting of disabling symptoms. Recent improvements in treatment efficacy have been shown in studies that target regions by mapping individual anatomy and connectivity patterns. This application, submitted in response to PAR-14-281, by a team of investigators at the forefront of understanding NVS disorders, will comprehensively characterize NVS spectrum disorders using the RDoC framework, focusing on brain circuits important in pathophysiology across the spectrum of loss and responses to sustained threat. By implementing neuroimaging assessment on a single Prisma scanner optimized for compatibility with the Human Connectome Protocol (HCP) and by collecting demographic data, neurocognitive data using the NIH Toolbox and Penn Computerized Neurocognitive Battery (CNB), and DNA samples, along with specialized assessments pertinent to NVS disorders, we will expand the HCP database with a highly significant pathophysiology sample for human health. These goals will be achieved by recruiting 50 control participants and 200 participants with anxious misery symptoms from the Outpatient Clinics of the University of Pennsylvania, where they will undergo an extensive multi-modal assessment to characterize the cross-sectional phenomenology of these NVS domains and a one-year followup to assess subsequent symptoms. The proposed project has both objectives and hypotheses. The main objective is to acquire and make public a vast database of brain imaging and behavioral data from patients with anxious misery as well as innovative new tools to analyze brain connectome changes. This objective includes careful QA and harmonization procedures. The main hypothesis to be tested is that severity of responses to sustained threat and loss correlate with dissociable circuit abnormalities in the structural and functional connectome; further, these abnormalities will predict course of illness.